Tumor cell invasion, the process by which tumor cells break away from the primary tumor and spread to distant organs, signals a transition to more advanced disease and greatly contributes to the lethality of many cancer types. The migration of single tumor cells has been well described, but mounting evidence suggests that tumor cells also migrate as a collective, or a group of cells that maintain adhesion and communication through cellular junctions. Cells migrating as a collective have been reported to invade more deeply into organs and to disperse into multiple tissue types. One hallmark of the most common malignant brain tumor, glioblastoma (GBM), is the invasion of tumor cells into the brain parenchyma, a characteristic that greatly contributes to the high rate of tumor recurrence after therapy. Our inability to successfully treat GBM is also driven by the presence of a therapeutically resistant population of self-renewing cells termed cancer stem cells (CSCs). CSCs have been shown to have an enhanced ability to migrate compared with non-stem tumor cells (non-CSCs), although the mechanisms by which CSCs invade and the consequences of this invasion have yet to be determined. The translational goal of this project is to conduct mechanistic studies into collective cell migration by CSCs and to determine the impact of this invasion on GBM progression. Based on our preliminary data showing collective cell migration of CSCs, we hypothesize that collective cell invasion is essential for GBM growth and can be disrupted by compromising the molecular processes governing collective cell invasion. To gain insight into these molecular processes, we performed a screen in Drosophila and identified novel genes responsible for collective invasion. Using an integrative approach spanning Drosophila development to human CSC models, we will interrogate this hypothesis by investigating the following aims: 1) that collective invasion requires dynamic cell-cell junctions and adhesion and 2) that disrupting collective cell invasion decreases GBM growth and increases the efficacy of standard-of-care therapy. The long-term goal of this project is to translate the information gained about collective cell migration and invasion of GBM CSCs to inhibition strategies useful as clinical therapies.